Project Summary The flexible application of rules according to context is a critical component of healthy cognition. For example, most people can apply different recycling rules in different cities. Inflexibility in rule selection is a salient feature of a number neurological disorders impacting mental health, including obsessive compulsive disorder, depression and drug abuse. Clinicians and scientists lack a clear characterization of the mechanistic factors that underlie the development of maladaptive behavioral inflexibility. I introduce the term rule habit to describe inflexibility in rule selection. Habits have two key consequences: they improve performance of the habitized action, and they impair performance of alternatives. Habits allow you to drive on a familiar route without paying attention, while interfering with your ability to make detours if your plans change. Similarly, a rule habit has two consequences in our task: 1) Facilitated execution of the habitized rule and 2) impaired execution of the alternative rule. This proposal uses converging causal neuroimaging and transcranial magnetic stimulation (TMS) tools to target mechanisms thought to contribute to rule habits. Both Aims use a task in which subjects are cued to apply one of two possible rules to a perceptual stimulus. Aim 1 tests whether reward reinforcement of a neural network representing a rule is sufficient to create a rule habit. I will use established methods to define networks representing each rule in prefrontal cortex. I will use real-time functional magnetic resonance imaging (rtfMRI) to trigger reward delivery during periods of elevated activation in one of the two rule networks. I predict that performance of the targeted rule will improve while performance of the non-targeted rule will be impaired. Aim 2 tests whether increasing synaptic plasticity in the inferior frontal sulcus (IFS), which represents rules, is sufficient to enhance the acquisition of a rule habit. I will use noninvasive neurostimulation, intermittent theta-burst TMS (tbTMS), to transiently reduce the threshold for synaptic plasticity in the targeted region of cortex. Subjects will receive tbTMS to either IFS or somatosensory cortex (S1), a control region. After treatment with tbTMS, subjects will undergo behavioral training on one rule. I predict that the training will create a rule habit for both the IFS and S1 groups, but that tbTMS over IFS will cause a stronger rule habit. The proposed techniques are innovative strategies for addressing how rule habits emerge as well as invaluable fellowship training goals. The Sponsor?s lab and UC Berkeley have abundant support and expertise for acquiring this training. The application of non-invasive neurotriggering and neurostimulation techniques will allow directional delineation of neural mechanisms of rule habits, unachievable with common correlational (i.e., neuroimaging) techniques alone. The proposed studies lay the foundation for future work that will investigate how neurostimulation can be used to disrupt maladaptive behavioral inflexibility in both health and disease.